Angiogenesis is a fundamental process by means of which new blood vessels are formed. This process is essential in multiple normal physiological phenomena such as reproduction, development and even cicatrisation.
The formation of neovessels by endothelial cells, involves the migration, growth and differentiation of endothelial cells. Regulation of these biological phenomena is linked to Insulin receptor substrate 1 (IRS-1), which is a cytoplasmic docking protein that functions as an essential signalling intermediate downstream of activated cell surface receptors, including insulin, insulin-like growth factor 1 (IGF-1), prolactin, growth hormone (GH), vascular endothelial growth factor (VEGFA) receptors, members of the integrin receptor family, and select cytokine receptors.
The normal cornea is devoid of both blood and lymphatic vessels. This avascularity is evolutionary highly conserved to maintain transparency and visual acuity. Nonetheless due to a variety of severe inflammatory diseases the cornea can become invaded by pathologic blood and lymphatic vessels. Inflammatory diseases of the eye, usually linked to pathologic corneal neovascularization, not only reduce corneal transparency, but also are a major risk factor for corneal transplantation.
Those inflammatory diseases of the eyes can be initiated by contact lens misuse, pseudomonas keratitis, herpes simplex keratitis, herpes zoster keratitis, Fuchs-Stevens-Johnson syndrome, prior surgery, alkali burns, graft rejection, degenerative disorders, as well as exposure to ultraviolet light such as sunlight or sunlamps, exposure to other intense light sources such as welding arcs or snow or water reflections, dry eyes caused by an eyelid disorder or insufficient tear formation, a foreign object in the eye, a vitamin A deficiency, or a reaction to eyedrops, eye cosmetics, pollution, or airborne particles such as dust, pollen, mold, or yeast.
In addition, host corneal neovascularization (both pre- as well as post-operatively) is one of the strongest risk factors for subsequent immune rejections after corneal grafting. Corneal graft rejection is primarily a cell-mediated immune response controlled by T cells. Normal corneal immune privilege can be eroded by neovascularisation, especially if accompanied by the sequelae of ocular inflammation and raised intraocular pressure. This is because if neovascularisation is present either before or after a corneal graft, the growth of new blood vessels provides a route of entry for immune-mediating cells to the graft, while the growth of new lymphatic vessels enables the exit of APCs and antigenic material from the graft to regional lymph nodes. The cornea consequently becomes infiltrated with and sensitized to immune reaction mediators. Therefore, although not an immune reaction in itself neovascularisation induces an immune response that can lead to immunological corneal graft rejection.
Conventional therapy, based on corticoids and immunosuppressants, is only partly effective in inhibiting corneal neovascularization. Corticosteroids and immunosuppressive therapy are used but are not very effective and have numerous side effects. There is therefore a need for alternative therapeutic approaches. The inventors previously described in U.S. Pat. No. 7,417,033 a pharmaceutical composition comprising the antisense oligonucleotide GS-101.
GS-101 is a 25 mer phosphorothioate with a molecular weight of 8,036 Da of the following sequence:
5′-TCTCCGGAGGGCTCGCCATGCTGCT-3′(SEQ ID NO : 1)There was still a need to define more precisely the dose and regimen at which said pharmaceutical composition is tolerable, efficient and optimal for preventing, stabilizing and/or inhibiting blood and lymph vascularization in a subject in need thereof.